Antitransforming growth factor-beta therapy in fibrosis: recent progress and implications for systemic sclerosis.
OBJECTIVE
Transforming growth factor-beta (TGF-beta) is required for tissue homeostasis but is also implicated in disease processes including fibrosis, and thus represents a molecular target for therapy.


RESULTS
Multiple strategies for inhibiting excessive TGF-beta function exist. The three principal platforms are RNA-based technologies, monoclonal antibodies and small molecules. Monoclonal antibodies targeting TGF-beta have been used in a small clinical trial, with disappointing results to date. Antibodies to the alphavbeta6 integrin prevent local activation of latent TGF-beta and show promise in preclinical studies. Over a dozen small molecules inhibit the kinase activity of TGF-beta receptors. Several commonly used drugs appear to have unanticipated anti-TGF-beta activity and may therefore have a role in antifibrotic therapy. Because TGF-beta has important physiological functions, inhibiting its activity might potentially lead to aberrant immune activation, epithelial hyperplasia and impaired wound healing; spontaneous autoimmunity in particular is a concern in an autoimmune disease such as systemic sclerosis. Novel insights from DNA microarray analysis and genetic polymorphisms in TGF-beta signaling will aid in defining patient populations most likely to respond to anti-TGF-beta treatment.


CONCLUSIONS
Anti-TGF-beta therapies promise to have a major impact in systemic sclerosis. Significant concerns regarding efficacy and safety need to be addresed. The identification of optimal candidates for therapy, and of biomarkers of safety and efficacy, are critical challenges ahead.
Varga
John
J
Department of Medicine and Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA. j-varga@northwestern.edu
Pasche
Boris
B
D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D005355:Fibrosis; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D012595:Scleroderma, Systemic / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D015398:Signal Transduction; D051785:Smad Proteins / Q000037:antagonists & inhibitors; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*
D000911:Antibodies, Monoclonal; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I